Esophageal Speech for a Patient with Amyotrophic Lateral Sclerosis Who Underwent a Central-part Laryngectomy to Prevent Aspiration: A Case Report.

Background: To prevent aspiration, patients with irreversible dysphagia may undergo surgeries that separate the esophagus and trachea. Such interventions result in loss of vocal function and require alternative communication methods. We report a patient with amyotrophic lateral sclerosis (ALS) who used esophageal speech after receiving a central-part laryngectomy (CPL) to prevent aspiration. Case: A 64-year-old woman with ALS was admitted to our hospital. The patient maintained good cognitive and oral function and presented with mild dysarthria and dysphagia. Faced with rapidly worsening respiratory distress, saliva aspiration, and excessive sputum, she underwent a tracheostomy on the premise of invasive ventilation. Subsequently, the patient began using a voice-generating application for communication. Given the patient's sincere hope to prevent aspiration and aspiration pneumonia, achieve safe oral intake, and decrease caregiver burden for frequent suctioning, the patient underwent a CPL. Following surgery, belching was observed during meals, and the patient could phonate when she belched. This finding led to four speech therapy sessions to practice esophageal speech, allowing the patient to use the pseudo-speech technique for short conversations. Removal of the entire cricoid cartilage in the CPL decreases the upper esophageal sphincter (UES) pressure, thereby allowing air to easily pass through the UES. Therefore, the patient could use the air as a sound source for esophageal speech without extensive training. Discussion: Esophageal speech may be an alternative to oral communication in patients undergoing CPL. Further research is warranted to generalize these findings to patients undergoing CPL.

Longitudinal change of comprehensive lower urinary tract symptoms and various types of urinary incontinence during robot-assisted radical prostatectomy.

AIMS: To clarify longitudinal change of lower urinary tract symptoms (LUTS) and various types of urinary incontinence following robot-assisted radical prostatectomy (RARP) using validated questionnaires. MATERIALS AND METHODS: The core lower urinary tract symptom score (CLSS) and the International Consultation on Incontinence Questionnaire (ICIQ)-Short Form (SF) questionnaires were administered to 607 consecutive, treatment-naïve men receiving RARP before and after surgery. The time course of comprehensive LUTS and various types of urinary incontinence, including stress-, urgency-, and urinary incontinence with no obvious reason, were evaluated. Continence recovery rates were compared for the different types of incontinence using Cox hazard regression analysis. RESULTS: After surgery, stress urinary incontinence (SUI) was reported most frequently (32% of cases) as the chief complaint with the most impact on daily life, as assessed by the CLSS questionnaire, followed by urgency urinary incontinence (UUI; 27% of cases). The rates of continence recovery differed among the different types of urinary incontinence, such as after urinating, when dressed, when asleep, when physically active or exercising, when coughing or sneezing, before reaching the toilet, and for no obvious reason. Incontinence for no obvious reason at 1 month after RARP was a strongest prognostic factor of delayed continence recovery (hazard ratio, 0.61; P < 0.0001), whereas patients reporting SUI and UUI gradually regained continence. CONCLUSIONS: Further time course on continent recovery after RARP would be more precisely predictable based on the incontinence status at one month postoperatively. Especially, incontinence with no obvious reason would be a significant factor for delayed recovery.

May perioperative ultrasound-guided pelvic floor muscle training promote early recovery of urinary continence after robot-assisted radical prostatectomy?

AIMS: The efficacy of perioperative pelvic floor muscle training (PFMT) for continence recovery after robot-assisted radical prostatectomy (RARP) remains unclear. Visualization of the bladder neck and urethra using transperineal ultrasound (US) may promote self-recognition of urethral closure during PFM contraction. This study aimed to examine whether transperineal US-guided PFMT promotes early recovery of post-RARP incontinence. METHODS: This prospective cohort study included 116 men undergoing RARP. All men were offered to undergo transperineal US-guided PFMT, and 36 men agreed. The protocol consisted of biofeedback PFMT using transperineal US before RARP and 1-month after RARP with verbal instruction of PFMT immediately after urethral catheter removal. The remaining 80 patients received verbal instruction for PFMT alone. Continence recovery was defined as the number of days requiring a small pad (20 g) per day by self-report. RESULTS: No differences were observed in demographic or peri-operative parameters between the two groups except the longer operative time in the US-guided PFMT group. The mean time until continence recovery was significantly shorter in the US-guided PFMT group (75.6 ± 100.0 days) than in the verbal-PFMT group (121.8 ± 132.0 days, P = 0.037). Continence recovery rates within 30 days were 52.8% (19/36) and 35.4% (28/80) in the US-guided PFMT and verbal-PFMT groups, respectively (P = 0.081). US-guided PFMT was associated with better postoperative continence status (adjusted hazard ratio [95% confidence interval]: 0.550 [0.336-0.900], P = 0.017). CONCLUSIONS: The results showed that transperineal US-guided PFMT perioperatively was associated with early recovery of urinary continence after RARP.

Influenza A (H3N2)-induced rhabdomyolysis complicating anterior compartment syndrome: Serial changes in muscle MRI T2 fat suppression imaging.

BACKGROUND: Rhabdomyolysis with influenza infection is rarely reported in adults. We report here influenza A induced rhabdomyolysis and anterior compartment syndrome (ACS). CASE REPORT: This case report describes a 43-year-old woman exhibiting influenza A induced rhabdomyolysis. High levels of creatine kinase (97,000 IU/L) and high titer of anti-influenza A virus antibody (H3N2) (320 ×) with negative anti-influenza B virus antibody were observed. T2 fat suppression muscle MRI imaging showed high-intensity signals in rectus femoris, vastus lateralis, adductor magnus, and semimembranosus (SM) muscles. The existence of ACS was suspected out. Muscle biopsy showed that fiber size variations exist without infiltration of inflammatory cells. The symptoms and muscle MRI findings of T2 fat suppression imaging was markedly improved. CONCLUSIONS: Muscle MRI T2 fat suppression imaging is a useful method to monitor influenza A induced rhabdomyolysis. We should keep in mind the possibilities of rhabdomyolysis and ACS in patients with influenza A infection presenting serious muscle pain.

Limbic encephalitis associated with anti-NH2-terminal of α-enolase antibodies: A clinical subtype of Hashimoto encephalopathy.

Several types of autoantibodies have been reported in autoimmune limbic encephalitis (LE), such as antibodies against the voltage-gated potassium channel (VGKC) complex including leucine-rich glioma inactivated 1 (LGI1). We recently reported a patient with autoimmune LE and serum anti-NH2-terminal of α-enolase (NAE) antibodies, a specific diagnostic marker for Hashimoto encephalopathy (HE), who was diagnosed with HE based on the presence of antithyroid antibodies and responsiveness to immunotherapy. This case suggests that LE patients with antibodies to both the thyroid and NAE could be diagnosed with HE and respond to immunotherapy. The aim of this study was to clarify the clinicoimmunological features and efficacy of immunotherapy in LE associated with anti-NAE antibodies to determine whether the LE is a clinical subtype of HE.We examined serum anti-NAE antibodies in 78 LE patients with limbic abnormality on magnetic resonance imaging and suspected HE based on positivity for antithyroid antibodies. Nineteen of the 78 patients had anti-NAE antibodies; however, 5 were excluded because they were double positive for antibodies to the VGKC complex including LGI1. No antibodies against the N-methyl-D-aspartate receptor (NMDAR), contactin-associated protein 2 (Caspr2), γ-aminobutyric acid-B receptor (GABABR), or α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) were detected in the 19 patients. Among the remaining 14 who were positive only for anti-NAE antibodies, the median age was 62.5 (20-83) years, 9 (64%) were women, and 8 (57%) showed acute onset, with less than 2 weeks between onset and admission. Consciousness disturbance (71%) and memory disturbance (64%) were frequently observed, followed by psychiatric symptoms (50%) and seizures (43%). The frequency of these symptoms significantly differed between the acute- and subacute-onset groups. Abnormalities in cerebrospinal fluid and electroencephalogram were commonly observed (92% for both). Tumors were not identified in any cases. All patients responded to immunotherapy or spontaneously remitted, thereby fulfilling the criteria of HE.This study demonstrated that LE associated with anti-NAE antibodies is a nonparaneoplastic LE and various limbic symptoms that depend on the onset type. Favorable therapeutic efficacy suggests that this LE can be considered a clinical subtype of HE and that anti-NAE antibodies may be a promising indicator of the need for immunotherapy.

A case of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody-positive paraneoplastic necrotizing myopathy associated with advanced gastric cancer that responded to intravenous immunoglobulin therapy.

A 49-year-old woman presented with progressive muscle weakness of the limbs and dysphagia. Her past and family medical history were unremarkable and she did not take statins or any other medications. Laboratory tests showed that serum levels of creatine kinase were elevated (13,565 IU/l) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies were detected in the serum. Other autoantibodies to the nuclear (ANA), RNP, aminoacyl-tRNA synthetases (ARS), and signal recognition particle (SRP) were negative. Pathological analysis of the left biceps muscle revealed minimal lymphocytic infiltration into the muscle fibers together with many necrotic and regenerated fibers, which corresponded to necrotizing myopathy. Abdominal CT and upper gastrointestinal endoscopy showed an advanced gastric cancer with lymph node metastasis. The patient was subsequently diagnosed with anti-HMGCR antibody-positive paraneoplastic necrotizing myopathy associated with advanced gastric cancer. The patient underwent radical surgery to remove the cancer and was initially treated with oral prednisolone and intravenous methylprednisolone pulse therapy; however, her symptoms worsened and she became bedridden. After an additional treatment with intravenous immunoglobulin (IVIg), she showed noticeable improvements in muscle strength and dysphagia and became ambulatory. This case and recent case-series studies suggest that anti-HMGCR antibody-positive necrotizing myopathy may be included in paraneoplastic syndrome and that physicians should screen for malignant tumors in patients with anti-HMGCR antibody-positive necrotizing myopathy. Moreover, IVIg can be a useful therapy in patients with anti-HMGCR antibody-positive paraneoplastic necrotizing myopathy who show refractoriness to tumor resection and corticosteroid therapies.

Pioglitazone prevents tau oligomerization.

Tau aggregation and amyloid ß protein (Aß) deposition are the main causes of Alzheimer's disease (AD). Peroxisome proliferator-activated receptor γ (PPARγ) activation modulates Aß production. To test whether the PPARγ agonist pioglitazone (PIO) is also effective in preventing tau aggregation in AD, we used a cellular model in which wild-type tau protein (4R0N) is overexpressed (M1C cells) (Hamano et al., 2012) as well as primary neuronal cultures. PIO reduced both phosphorylated and total tau levels, and inactivated glycogen synthase kinase 3ß, a major tau kinase, associated with activation of Akt. In addition, PIO decreased cleaved caspase3 and C-terminal truncated tau species by caspase, which is expected to decrease tau aggregation. A fractionation study showed that PIO reduced high molecular-weight (120 kDa), oligomeric tau species in Tris Insoluble, sarkosyl-soluble fractions. Tau decrease was reversed by adding GW9662, a PPARγ antagonist. Together, our current results support the idea that PPARγ agonists may be useful therapeutic agents for AD.

Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias.

In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto's encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Miller Fisher syndrome, ataxia associated with systemic lupus erythematosus, and paraneoplastic cerebellar degeneration. Humoral mechanisms, cell-mediated immunity, inflammation, and vascular injuries contribute to the cerebellar deficits in immune-mediated cerebellar ataxias.

Haploinsufficiency of CSF-1R and clinicopathologic characterization in patients with HDLS.

OBJECTIVE: To clarify the genetic, clinicopathologic, and neuroimaging characteristics of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) with the colony stimulating factor 1 receptor (CSF-1R) mutation. METHODS: We performed molecular genetic analysis of CSF-1R in patients with HDLS. Detailed clinical and neuroimaging findings were retrospectively investigated. Five patients were examined neuropathologically. RESULTS: We found 6 different CSF-1R mutations in 7 index patients from unrelated Japanese families. The CSF-1R mutations included 3 novel mutations and 1 known missense mutation at evolutionarily conserved amino acids, and 1 novel splice-site mutation. We identified a novel frameshift mutation. Reverse transcription PCR analysis revealed that the frameshift mutation causes nonsense-mediated mRNA decay by generating a premature stop codon, suggesting that haploinsufficiency of CSF-1R is sufficient to cause HDLS. Western blot analysis revealed that the expression level of CSF-1R in the brain from the patients was lower than from control subjects. The characteristic MRI findings were the involvement of the white matter and thinning of the corpus callosum with signal alteration, and sequential analysis revealed that the white matter lesions and cerebral atrophy relentlessly progressed with disease duration. Spotty calcifications in the white matter were frequently observed by CT. Neuropathologic analysis revealed that microglia in the brains of the patients demonstrated distinct morphology and distribution. CONCLUSIONS: These findings suggest that patients with HDLS, irrespective of mutation type in CSF-1R, show characteristic clinical and neuroimaging features, and that perturbation of CSF-1R signaling by haploinsufficiency may play a role in microglial dysfunction leading to the pathogenesis of HDLS.

Development of a methodology using gas chromatography-combustion-isotope ratio mass spectrometry for the determination of the carbon isotope ratio of caffeine extracted from tea leaves (Camellia sinensis).

RATIONALE: Compound-specific isotope analysis (CSIA) of the extracted caffeine can be used to determine the authenticity of the origin of tea. Elemental analysis-isotope ratio mass spectrometry (EA-IRMS), which is widely used to measure the carbon isotope ratio of caffeine, has a strict requirement for the purity of the extracted caffeine. To obtain high-purity caffeine from tea leaves, the conventional extraction process has to be repeated and usually takes about 5-6 h. To improve the measurement of the carbon isotope ratio of caffeine, a more rapid and accurate measuring method is needed. METHODS: An analytical protocol was developed for the determination of the carbon isotope ratio of caffeine from tea leaves using gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) combined with our extraction process. The procedure to extract caffeine and determine its carbon isotope ratio takes around 1.5 h. RESULTS: The standard deviation of the method is less than 0.1‰ (1σ). The measured carbon isotope ratios were not influenced by the amount of caffeine injected (0.08-0.62 µg) or by the extraction yield of caffeine from the tea leaves. CONCLUSIONS: The carbon isotope ratios of caffeine from eight tea cultivars were determined using the protocol.

Transient elevation of international normalized ratio during cisplatin-based chemotherapy in patients who are taking warfarin.

OBJECTIVE: To report 2 cases of a probable interaction between cisplatin and warfarin. CASE SUMMARY: Two cases of transient elevation of international normalized ratio (INR) during irinotecan (60 mg/m2 on days 1, 8, and 15) plus cisplatin (60 mg/m2 on day 1) chemotherapy with concomitant warfarin are presented. In both cases, warfarin dosages were stable at the therapeutic target range prior to initiation of chemotherapy. Granisetron hydrochloride (3 mg on days 1, 8, and 15) and dexamethasone (13.2 mg on day 1 and 6.6 mg on days 2, 3, 8, and 15) were used prior to irinotecan administration in both patients. In addition, aprepitant was administered to both patients for 3-5 days with cisplatin. One of these patients also received aprepitant with irinotecan on days 8 and 15. During chemotherapy, INR was transiently elevated almost 1.5-fold over baseline level on day 3. This variation did not occur in subsequent irinotecan cycles on days 8 and 15. The timing of these increases was similar in each of the cycles. DISCUSSION: Cisplatin was the common drug in the cases presented and therefore could be related to the INR elevations. To our knowledge, these are the first reports of an interaction between warfarin and irinotecan-cisplatin chemotherapy, but reports of a similar interaction with chemotherapy including platinum derivatives exist. Use of the Horn Drug Interaction Probability Scale indicated a probable interaction between warfarin and cisplatin. CONCLUSIONS: Cisplatin might affect the anticoagulation function of warfarin. Careful INR monitoring is necessary during antineoplastic chemotherapy with cisplatin in patients taking warfarin.

[Effects of voriconazole and vascular lesions in invasion of aspergillosis into the central nerve system].

We report 2 patients showing invasion of aspergillosis into the central nerve system (CNS). Patient 1, an 81-year-old woman, underwent surgery for sphenoidal sinusitis. She developed cerebral infarction with unconsciousness on 12th postoperative day. CSF examination demonstrated pleocytosis with increased protein and aspergillus antigen. She was diagnosed as having invasion of aspergillosis into the CNS, and was treated with voriconazole. Her clinical manifestations and CSF findings markedly improved. However, the effects of voriconazole gradually attenuated and she demonstrated recurrence of the cerebral infarction. After 2 months, she died of systemic aspergillosis and sepsis. Autopsy studies. Severe atherosclerotic changes with calcification were demonstrated in the bilateral carotid and basilar arteries, and many aspergillus were clustered in the vessel walls. Granulomatous inflammatory lesions with aspergillus were also demonstrated in the area surrounding the chiasm. There were no massive infarcts or bleeding in the brain, but multiple small infarcts were present. Patinet 2, a 64-year-old man, showing bilateral visual loss, was receiving treatment with corticosteroids under a diagnosis of optic neuritis. Two weeks later, he developed cerebral infarction. CSF examination showed pleocytosis with increased protein and aspergillus antigen. He was diagnosed as having invasive aspergillosis from the sphenoidal sinusitis into the CNS. He was treated with voriconazole, and unconsciousness and CSF findings improved transiently. However, he developed a recurrence of the brain infarction and pneumonia and finally died 6 months later. Treatment by voriconazole was definitely effective in both patients, but both patients died of recurrent cerebral infarction, possibly due to resistance for voriconazole, or developing multicellular filamentous biofilms. Voriconazole is recommended as the first choice of antifungal agents for aspergillosis. Aspergillus infection is strongly invasive into arterial vessels. It is important to consider the possible occurrence of cerebrovascular disease when treating invasion of aspergillosis into the CNS.

Two novel mutations in the ED1 gene in Japanese families with X-linked hypohidrotic ectodermal dysplasia.

X-linked hypohidrotic ectodermal dysplasia (XLHED), which is characterized by hypodontia, hypotrichosis, and hypohidrosis, is caused by mutations in ED1, the gene encoding ectodysplasin-A (EDA). This protein belongs to the tumor necrosis factor ligand superfamily. We analyzed ED1 in two Japanese patients with XLHED. In patient 1, we identified a 4-nucleotide insertion, c.119-120insTGTG, in exon 1, which led to a frameshift mutation starting from that point (p.L40fsX100). The patient's mother was heterozygous for this mutation. In patient 2, we identified a novel missense mutation, c.1141G>C, in exon 9, which led to a substitution of glycine with arginine in the TNFL domain of EDA (p.G381R). This patient's mother and siblings showed neither symptoms nor ED1 mutations, so this mutation was believed to be a de novo mutation in maternal germline cells. According to molecular simulation analysis of protein structure and electrostatic surface, p.G381R increases the distance between K375 in monomer A and K327 in monomer B, which suggests an alteration of overall structure of EDA. Thus, we identified two novel mutations, p.L40fsX100 and p.G381R, in ED1 of two XLHED patients. Simulation analysis suggested that the p.G381R mutation hampers binding of EDA to its receptor via alteration of overall EDA structure.

Molecular cloning, expression, and characterization of adenylate isopentenyltransferase from hop (Humulus lupulus L.).

A cDNA encoding adenylate isopentenyltransferase (AIPT) was cloned and sequenced from cones of hop (Humulus lupulus L.) by RT-PCR using oligonucleotide primers based on the conserved sequences of Arabidopsis thaliana AIPT isozymes (AtIPT1, AtIPT3, AtIPT4, AtIPT5, AtIPT6, AtIPT7 and AtIPT8). A full-length cDNA contained a 990-bp open reading frame encoding a molecular mass of 36,603 Da protein with 329 amino acids. Further, DNA sequencing of genomic DNA revealed absence of introns in the frame. On Southern blot analysis, a single AIPT gene was detected in H. lupulus, while RT-PCR analyses demonstrated that the gene was equally expressed in almost all tissues in the plant including roots, stems, leaves and cones. The deduced amino acid sequence shares 38-51% identity to those of A. thaliana AtIPTs. A recombinant enzyme expressed in Escherichia coli catalyzed isopentenyl transfer reaction from dimethylallyldiphosphate (DMAPP) to the N6 amino group of adenosine monophosphate (AMP), adenosine diphosphate (ADP) and adenosine triphosphate (ATP), respectively. In contrast, other nucleotides; guanosine monophosphate (GMP), inosine monophosphate (IMP), cytosine monophosphate (CMP), uridine monophosphate (UMP), were not accepted as a substrate. Interestingly, steady-state kinetic analyses revealed that the isopentenylation of ADP and ATP were more efficient than that of AMP as previously reported for A. thaliana AtIPT4. Finally, H. lupulus AIPT contains the putative ATP/GTP binding motif at the N-terminal as in the case of other known isopentenyltransferases. Site-directed mutagenesis of a conserved Asp62, located right after the ATP/GTP binding motif, with Ala resulted in complete loss of enzyme activity.